Paclitaxel sensitivity of breast cancer cells with constitutively active NF-κB is enhanced by IκBα super-repressor and parthenolide
Paclitaxel sensitivity of breast cancer cells with constitutively active NF-κB is enhanced by IκBα super-repressor and parthenolide
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DOI：
10.1038/sj.onc.1203768
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发表时间：
2000-08-24
期刊：
影响因子：
8
通讯作者：
Nakshatri, H
中科院分区：
文献类型：
--
作者：
Patel, NM;Nozaki, S;Nakshatri, H
转录因子核因子-κ B（NF-κ B）调节对肿瘤侵袭、转移和化学抗性重要的基因。正常情况下，NF-κ B通过胞质κ B（I κ B）蛋白保持隔离在非活性状态，NF-κ B易位至细胞核并在细胞暴露于生长因子和细胞因子时激活基因表达。我们和其他人先前已经表明NF-κ B在乳腺癌的亚群中是组成性活性的。在这项研究中，我们发现NF-κ B的组成性激活导致抗凋亡基因c-IAP 2和锰超氧化物歧化酶（Mn-SOD）在乳腺癌细胞中的过表达，此外，抗凋亡肿瘤坏死因子受体相关因子1（TRAF 1）和细胞死亡防御因子（DAD-1）的表达在某些乳腺癌细胞中受到NF-κ B的调节。我们还证明，NF-κ B诱导基因保护癌细胞免受紫杉醇的侵袭，因为与亲本细胞相比，修饰为过表达I κ B α的MDA-MB-231乳腺癌细胞需要较低浓度的紫杉醇来阻滞在细胞周期的G2/M期并进行凋亡。NF-κ B对紫杉醇敏感性的影响似乎是癌细胞特异性的，因为来自缺乏NF-κ B的p65亚基的胚胎和野生型同窝胚胎的正常成纤维细胞对紫杉醇诱导的G2/M细胞周期停滞不敏感。银胶菊，草药如小白菊（菊）的活性成分，通过抑制NF-κ B DNA结合活性和Mn-SOD表达模拟I κ B α的作用，并增加紫杉醇诱导的乳腺癌细胞凋亡。这些结果表明，具有抗炎特性的草药的活性成分可能有助于增加具有组成性活性NF-κ B的癌症对化疗药物的敏感性。
The transcription factor nuclear factor-kappa B (NF-KB) regulates genes important for tumor invasion, metastasis and chemoresistance. Normally, NF-kappa B remains sequestered in an inactive state by cytoplasmic inhibitor-of-kappa B (I kappa B) proteins, NF-kappa B translocates to nucleus and activates gene expression upon exposure of cells to growth factors and cytokines, We and others have shown previously that NF-kappa B is constitutively active in a subset of breast cancers. In this study, we show that constitutive activation of NF-kappa B leads to overexpression of the antiapoptotic genes c-inhibitor of apoptosis 2 (c-IAP2) and manganese superoxide dismutase (Mn-SOD) in breast cancer cells, Furthermore, expression of the antiapoptotic tumor necrosis factor receptor associated factor 1 (TRAF1) and defender-against cell death (DAD-1) is regulated by NF-kappa B in certain breast cancer cells. We also demonstrate that NF-kappa B-inducible genes protect cancer cells against paclitaxel as MDA-MB-231 breast cancer cells modified to overexpress I kappa B alpha required lower concentrations of paclitaxel to arrest at the G2/M phase of the cell cycle and undergo apoptosis when compared to parental cells. The effect of NF-kappa B on paclitaxel-sensitivity appears to be specific to cancer cells because normal fibroblasts derived from embryos lacking p65 subunit of NF-kappa B and wild type littermate embryos were insensitive to paclitaxel-induced G2/M cell cycle arrest. Parthenolide, an active ingredient of herbal remedies such as feverfew (tanacetum parthenium), mimicked the effects of I kappa B alpha by inhibiting NF-kappa B DNA binding activity and Mn-SOD expression, and increasing paclitaxel-induced apoptosis of breast cancer cells. These results suggest that active ingredients of herbs with anti-inflammatory properties may be useful in increasing the sensitivity of cancers with constitutively active NF-kappa B to chemotherapeutic drugs.